The Inorganic Nitrate and eXercise performance in Heart Failure (iNIX-HF): - a phase II clinical trial

无机硝酸盐和运动在心力衰竭中的表现 (iNIX-HF)：- II 期临床试验

基本信息

批准号：
10449833
负责人：
ANDREW R COGGAN
金额：
$ 80.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449833
关键词：
Activities of Daily Living Acute Aerobic Aerobic Exercise Affect Biological Availability Breath Tests Cachexia Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Case Report Form Chronic Cities Clinical Clinical Trials Clinical Trials Data Monitoring Committees Clinical trial protocol document Consent Forms Data Databases Development Disease Disease Outcome Dose Double-Blind Method EFRAC Effectiveness Enrollment Event Exercise Exercise Test Exercise Tolerance FDA approved Failure Functional disorder Future Goals Grant Half-Life Heart Heart failure Hospitalization Hour Human Impairment Infrastructure Ingestion Institutional Review Boards Iowa Isotonic Exercise Kansas Left Left Ventricular Ejection Fraction Manuals Measurement Measures Minnesota Monitor Muscle Muscle Contraction Muscle function New York Nitrates Nitric Oxide Nitrites Nitrogen Dioxide Nursing Protocols Oral Oxygen Consumption Participant Pathway interactions Patients Performance Persons Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase II Clinical Trials Phenotype Physicians Placebo Control Placebos Plasma Procedures Production Prognosis Protocols documentation Pump Questionnaires Randomized Randomized Clinical Trials Research Research Design Rest Safety Skeletal Muscle Speed Sum Surveys Symptoms Testing Time Translational Research Treatment Failure Universities Update Vasodilation Ventricular Visit arm base capsule clinical care clinical center dietary disability drug testing effective therapy effectiveness evaluation effectiveness testing exercise capacity hemodynamics improved mortality novel novel therapeutics operation phase 2 study phase 3 study physically handicapped primary endpoint quadriceps muscle recruit reduce symptoms respiratory gas safety testing screening secondary endpoint side effect skeletal abnormality targeted agent treadmill trial design

项目摘要

ABSTRACT Heart failure with reduced ejection fraction (HFrEF) affects ~3 million people in the U.S. and is a mortal and morbid disease. HFrEF impairs a patient’s ability to exercise and perform activities of daily living. Although weak cardiac pumping ability clearly contributes to chronic disability associated with HFrEF, abnormal skeletal muscle function in patients with HFrEF is also a key debilitating factor. Skeletal muscle is therefore a vital target for treatment of HFrEF. Dietary inorganic nitrate enhances aerobic exercise capacity and muscle power in patients with HFrEF, as demonstrated in our preliminary studies. The overarching aim of the proposed clinical trial is to determine whether inorganic nitrate in a once-a-day oral gelcap format, offers a new, safe, and effective treatment for ameliorating the impaired exercise performance due to HFrEF. The Aim of the R61 component of this grant is to set up the infrastructure necessary for the phase II clinical trial and to begin the trial. This includes compounding the inorganic nitrate (KNO3)/placebo capsules and all safety testing, obtaining Institutional Review Board approval, ClinicalTrials.gov registration, REDCap database development, Recruitment Enhancement Core (REC) engagement, Clinical Translational Research Unit (CTRU) project approval, enrollment and assessment and dose administration of the first subjects. The Aims of the R33 component are to determine the effectiveness of acute (2 hours after a single dose) and chronic (after 6 weeks of once-a-day dosing) KNO3 treatment (10mmol) vs. placebo on quadriceps muscle power and on aerobic exercise performance (V̇O2peak) in patients with HFrEF (left ventricular ejection fraction <45%). We hypothesize that both acute and chronic dosing of 10mmol of KNO3 will improve exercise performance in HFrEF. To test this hypothesis, we will perform a randomized, double-blind, placebo-controlled, parallel-arm design study. Patients with stable New York Heart Association class I-III HFrEF will undergo screening and phenotyping before completing baseline peak muscle power and aerobic performance measurements. On visit 2, subjects will receive a single dose (1 capsule) of their assigned treatment (10mmol KNO3 or placebo) and will repeat the measurements of exercise performance after 2h. Subjects will then continue with their assigned treatment (KNO3 or placebo, 1 capsule daily) for 6 weeks. On visit 3, subjects will repeat the tests of exercise performance. The primary endpoints are maximum quadriceps muscle power, measured using an isokinetic dynamometer, and aerobic exercise performance, based on V̇O2peak. Max exercise time and max muscle velocity, tolerability and safety of KNO3 vs. placebo treatment and their effects on hemodynamics, plasma nitrate, plasma nitrite, breath nitric oxide (NO), and heart failure symptoms (using well-validated questionnaires) will also be quantified in this phase II, single-center clinical trial. The potential impact of finding a new, safe and effective treatment that helps millions of patients beat the physical disability of HFrEF is enormous.

抽象的射血分数降低的心力衰竭 (HFrEF) 影响美国约 300 万人，是一种致命的疾病 HFrEF 会损害患者的运动和日常生活活动能力，尽管其能力较弱。心脏泵血能力明显导致与 HFrEF、骨骼肌异常相关的慢性残疾 HFrEF 患者的功能也是一个关键的衰弱因素，因此骨骼肌是治疗的重要目标。膳食无机硝酸盐的治疗可增强患者的有氧运动能力和肌肉力量。正如我们的初步研究所示，拟议的临床试验的总体目标是确定每天一次口服胶囊形式的无机硝酸盐是否提供了一种新的、安全的和有效的改善因 HFrEF 导致的运动能力受损的治疗。这笔赠款的 R61 部分的目的是建立第二阶段所需的基础设施临床试验并开始试验，这包括配制无机硝酸盐 (KNO3)/安慰剂胶囊和所有安全测试、获得机构审查委员会批准、ClinicalTrials.gov 注册、REDCap 数据库开发、招聘增强核心 (REC) 参与、临床转化研究单位 (CTRU) 项目批准、入组和评估以及第一批受试者的剂量管理。 R33 成分的目的是确定急性（单剂量后 2 小时）的有效性股四头肌慢性（每日一次给药 6 周后）KNO3 治疗 (10mmol) 与安慰剂对比 HFrEF（左心室射血分数）患者的功率和有氧运动表现（V̇O2peak） <45%），我们敢说急性和慢性服用 10mmol KNO3 都会改善运动。为了检验这一假设，我们将进行一项随机、双盲、安慰剂对照的试验。具有稳定的纽约心脏协会 I-III 级 HFrEF 的患者将接受平行臂设计研究。在完成基线峰值肌肉力量和有氧运动表现之前进行筛选和表型分析在第 2 次访视时，受试者将接受单剂量（1 粒胶囊）指定的治疗（10mmol）。 KNO3 或安慰剂）并将在 2 小时后重复测量运动表现，然后受试者将继续。接受指定的治疗（KNO3 或安慰剂，每天 1 粒胶囊），持续 6 周。在第 3 次访视时，受试者将重复该治疗。运动表现测试的主要终点是最大股四头肌力量，通过测量来测量。等速测功机和基于 V̇O2peak 的有氧运动表现。 KNO3 与安慰剂治疗的肌肉速度、耐受性和安全性及其对血流动力学、血浆的影响硝酸盐、血浆亚硝酸盐、呼吸一氧化氮 (NO) 和心力衰竭症状（使用经过充分验证的问卷）还将在这项 II 期单中心临床试验中量化寻找新的、安全的潜在影响。帮助数百万患者战胜 HFrEF 身体残疾的有效治疗是巨大的。